Erectile dysfunction (ED) affects 1 in 5 men in the United States and has annual healthcare expenditures exceeding $4 billion. The treatment paradigm for ED involves a trial-and-error approach, with the costs of repeated clinic visits now exceeding surgical costs. No candidate molecule has shown clinical potential as a marker of high risk or disease stratification to facilitate either targeted therapy or the prevention of ED. Genetic approaches can accelerate such efforts through mechanistic, drug, and biomarker discovery. Unexplained variation in ED risk points toward genetic influences, supported by heritability of 0.32 in the Vietnam Era Twin (VET) Registry. Small studies in selected populations suggest the influence of specific variants on ED risk and on response to the phosphodiesterase type 5 inhibitor (PDE5i) sildenafil citrate. Without replication, these findings cannot drive translational advances in care. We hypothesize that genetic variants are associated with ED pathogenesis and progression/severity. Collaboration within the Kaiser Permanente (KP) Research Program in Genes, Environment and Health (RPGEH), electronic Medical Record and Genomics (eMERGE) Network, and the Multiethnic Study of Atherosclerosis (MESA) will combine innovative phenotyping with existing and imputed genotypes in a cost-effective strategy of proposed genome-wide association studies (GWAS). We will also focus on elucidating the genetic contribution to ED among diabetic men, a high-risk population. Identifying genes and molecular networks associated with ED and clinical measures of severity will substantially advance our understanding of the disease mechanisms of ED.